Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001043131 | SCV001206847 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2022-03-03 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 841001). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 304 of the SMARCA4 protein (p.Pro304His). This variant is not present in population databases (gnomAD no frequency). |
| Ambry Genetics | RCV002372777 | SCV002686016 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-25 | criteria provided, single submitter | clinical testing | The p.P304H variant (also known as c.911C>A), located in coding exon 5 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 911. The proline at codon 304 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. |